Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.762.314
Filtrar
1.
Drug Dev Res ; 85(4): e22215, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38837718

RESUMO

Breast cancer is the second most frequent cancer among women. Out of various subtypes, triple-negative breast cancers (TNBCs) account for 15% of breast cancers and exhibit more aggressive characteristics as well as a worse prognosis due to their proclivity for metastatic progression and limited therapeutic strategies. It has been demonstrated that AMP-activated protein kinase (AMPK) has context-specific protumorigenic implications in breast cancer cells. A set of glucosyltriazole amphiphiles, consisting of acetylated (9a-h) and unmodified sugar hydroxyl groups (10a-h), were synthesized and subjected to in vitro biological evaluation. Among them, 9h exhibited significant anticancer activity against MDA-MB-231, MCF-7, and 4T1 cell lines with IC50 values of 12.5, 15, and 12.55 µM, respectively. Further, compound 9h was evaluated for apoptosis and cell cycle analysis in in vitro models (using breast cancer cells) and antitumour activity in an in vivo model (orthotopic mouse model using 4T1 cells). Annexin-V assay results revealed that treatment with 9h caused 34% and 28% cell death at a concentration of 15 or 7.5 µM, respectively, while cell cycle analysis demonstrated that 9h arrested the cells at the G2/M or G1 phase in MCF-7, MDA-MB-231 and 4T1 cells, respectively. Further, in vivo, investigation showed that compound 9h exhibited equipotent as doxorubicin at 7.5 mg/kg, and superior efficacy than doxorubicin at 15 mg/kg. The mechanistic approach revealed that 9h showed potent anticancer activity in an in vivo orthotopic model (4T1 cells) partly by suppressing the AMPK activation. Therefore, modulating the AMPK activation could be a probable approach for targeting breast cancer and mitigating cancer progression.


Assuntos
Proteínas Quinases Ativadas por AMP , Antineoplásicos , Apoptose , Transdução de Sinais , Triazóis , Humanos , Feminino , Animais , Proteínas Quinases Ativadas por AMP/metabolismo , Triazóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Camundongos , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Camundongos Endogâmicos BALB C , Células MCF-7 , Proliferação de Células/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Parasite Immunol ; 46(6): e13039, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38838041

RESUMO

Ticks are notorious blood-sucking ectoparasites that affect both humans and animals. They serve as a unique vector of various deadly diseases. Here, we have shown the roles of the receptor for advanced glycation end products (RAGE) during repeated infestations by the tick Haemaphysalis longicornis using RAGE-/- mice. In primary infestation, a large blood pool developed, which was flooded with numerous RBCs, especially during the rapid feeding phase of the tick both in wild-type (wt) and RAGE-/- mice. Very few inflammatory cells were detected around the zones of haemorrhage in the primary infestations. However, the number of inflammatory cells gradually increased in the subsequent tick infestations, and during the third infestations, the number of inflammatory cells reached to the highest level (350.3 ± 16.8 cells/focus). The site of attachment was totally occupied by the inflammatory cells in wt mice, whereas very few cells were detected at the ticks' biting sites in RAGE-/- mice. RAGE was highly expressed during the third infestation in wt mice. In the third infestation, infiltration of CD44+ lymphocytes, eosinophils and expression of S100A8 and S100B significantly increased at the biting sites of ticks in wt, but not in RAGE-/- mice. In addition, peripheral eosinophil counts significantly increased in wt but not in RAGE-/- mice. Taken together, our study revealed that RAGE-mediated inflammation and eosinophils played crucial roles in the tick-induced inflammatory reactions.


Assuntos
Inflamação , Ixodidae , Camundongos Knockout , Receptor para Produtos Finais de Glicação Avançada , Infestações por Carrapato , Animais , Ixodidae/genética , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Receptor para Produtos Finais de Glicação Avançada/genética , Camundongos , Infestações por Carrapato/imunologia , Camundongos Endogâmicos C57BL , Feminino , Comportamento Alimentar , Haemaphysalis longicornis
3.
Cell Metab ; 36(6): 1320-1334.e9, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38838643

RESUMO

Circadian homeostasis in mammals is a key intrinsic mechanism for responding to the external environment. However, the interplay between circadian rhythms and the tumor microenvironment (TME) and its influence on metastasis are still unclear. Here, in patients with colorectal cancer (CRC), disturbances of circadian rhythm and the accumulation of monocytes and granulocytes were closely related to metastasis. Moreover, dysregulation of circadian rhythm promoted lung metastasis of CRC by inducing the accumulation of myeloid-derived suppressor cells (MDSCs) and dysfunctional CD8+ T cells in the lungs of mice. Also, gut microbiota and its derived metabolite taurocholic acid (TCA) contributed to lung metastasis of CRC by triggering the accumulation of MDSCs in mice. Mechanistically, TCA promoted glycolysis of MDSCs epigenetically by enhancing mono-methylation of H3K4 of target genes and inhibited CHIP-mediated ubiquitination of PDL1. Our study links the biological clock with MDSCs in the TME through gut microbiota/metabolites in controlling the metastatic spread of CRC, uncovering a systemic mechanism for cancer metastasis.


Assuntos
Relógios Circadianos , Microbioma Gastrointestinal , Células Supressoras Mieloides , Animais , Camundongos , Células Supressoras Mieloides/metabolismo , Humanos , Metástase Neoplásica , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/microbiologia , Camundongos Endogâmicos C57BL , Masculino , Microambiente Tumoral , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/metabolismo , Feminino , Camundongos Endogâmicos BALB C , Linhagem Celular Tumoral
4.
Cell Metab ; 36(6): 1287-1301.e7, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38838641

RESUMO

Adipocytes in dermis are considered to be important participants in skin repair and regeneration, but the role of subcutaneous white adipose tissue (sWAT) in skin repair is poorly understood. Here, we revealed the dynamic changes of sWAT during wound healing process. Lineage-tracing mouse studies revealed that sWAT would enter into the large wound bed and participate in the formation of granulation tissue. Moreover, sWAT undergoes beiging after skin injury. Inhibition of sWAT beiging by genetically silencing PRDM16, a key regulator to beiging, hindered wound healing process. The transcriptomics results suggested that beige adipocytes in sWAT abundantly express neuregulin 4 (NRG4), which regulated macrophage polarization and the function of myofibroblasts. In diabetic wounds, the beiging of sWAT was significantly suppressed. Thus, adipocytes from sWAT regulate multiple aspects of repair and may be therapeutic for inflammatory diseases and defective wound healing associated with aging and diabetes.


Assuntos
Tecido Adiposo Branco , Pele , Cicatrização , Animais , Tecido Adiposo Branco/metabolismo , Camundongos , Pele/metabolismo , Pele/patologia , Camundongos Endogâmicos C57BL , Gordura Subcutânea/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Neurregulinas/metabolismo , Neurregulinas/genética , Masculino , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Tecido Adiposo Marrom/metabolismo , Adipócitos Bege/metabolismo , Macrófagos/metabolismo , Humanos , Miofibroblastos/metabolismo
5.
Pak J Biol Sci ; 27(5): 244-255, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38840465

RESUMO

<b>Background and Objective:</b> The RH3.5 was isolated from the rhizosphere of <i>Boesenbergia rotunda</i> (L.) Mansf. and identified to be <i>Streptomyces chartreusis</i> via analysis of its 16S rDNA sequence, chemotaxonomy and morphology. The aim of this study was to identify the major compounds of RH3.5 and assess their biological activities. <b>Materials and Methods:</b> Silica gel column chromatography and thin-layer chromatography were used to purify major compounds, elucidate 5,7,2'-trihydroxy-8-methoxyflavanone (compound <b>1</b>) and 5',2',5'-trihydroxy-7,8-dimethoxyflavanone (compound <b>2</b>). Subsequently, mass spectrometry and NMR techniques were used to identify the structure of these compounds. Antimicrobial, anti-inflammatory and cytotoxic properties were carried out using <i>in vitro</i> assays. <b>Results:</b> The bioassays revealed the antimicrobial effect of compounds <b>1</b> and <b>2</b> on MRSA and <i>Staphylococcus aureus</i>. The minimum inhibitory concentration and minimum bactericidal concentration was calculated in the range of 32-64 and 128-256 µg/mL, respectively. The compounds <b>1</b> and <b>2</b> also exhibited anti-inflammatory potential by inhibiting NO, IL-1ß and TNF-α production in LPS-stimulated RAW264.7 cells in a dose-dependent manner. Additionally, they had mild cytotoxic action against Vero and L929 cell lines with IC<sub>50</sub> values greater than 512 µg/mL. <b>Conclusion:</b> These findings showed that flavonoids of <i>Streptomyces</i> <i>chartreusis</i> RH3.5 exhibited antibacterial and anti-inflammatory activities with low cytotoxicity against healthy cells. Thorough research on these compounds could result in the creation of useful methods for treating microbial infections and acute inflammatory responses.


Assuntos
Antibacterianos , Anti-Inflamatórios , Flavonoides , Streptomyces , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/isolamento & purificação , Streptomyces/metabolismo , Flavonoides/farmacologia , Antibacterianos/farmacologia , Animais , Camundongos , Células RAW 264.7 , Testes de Sensibilidade Microbiana , Staphylococcus aureus/efeitos dos fármacos
6.
Anat Histol Embryol ; 53(4): e13064, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38841825

RESUMO

There are different strains of laboratory mouse used in many different fields. These strains differ anatomically. In order to determine these anatomical differences, shape analysis was conducted according to species. CD-1, C57bl/6 and Balb-c strains were preferred to study these differences. Forty-eight adult mouse strains belonging to these strains were utilized. The bones were photographed and geometric morphometry was applied to these photographs. Principal Component Analysis was applied to determine shape variations. In Principal component 1 for cranium, CD-1 and C57bl/6 strain groups showed different shape variations, while Balb-c strain group showed similar shape variations to the other strain groups. Principal Component 1 for the mandible separated the CD-1 and C57bl/6 strain groups in terms of shape variation. Principal Component 2 explained most of the variation between the C57bl/6 and CD-1 lineage groups. In PC1 for molars, the CD-1 group showed a different shape variation from the other groups. Mahalanobis distances and Procrustes distances were measured using Canonical variance analysis to explain the differences between the lineage groups. These measurements were statistically significant. For cranium, in canonical variate 1, CD-1 group of mouse and Balb-c group of mouse were separated from each other. In canonical variate 2, C57bl/6 group of mouse were separated from the other groups. For mandible, Balb-c group of mouse in canonical variate 1 and CD-1 group of mouse in canonical variate 2 were separated from the other groups. For molars, CD-1 group of mouse in canonical variate 1 and Balb-c group of mouse in canonical variate 2 were separated from the other groups. It was thought that these anatomical differences could be caused by genotypic factors as well as dietary differences and many different habits that would affect the way their muscles work.


Assuntos
Mandíbula , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Crânio , Animais , Crânio/anatomia & histologia , Camundongos/anatomia & histologia , Mandíbula/anatomia & histologia , Camundongos Endogâmicos BALB C/anatomia & histologia , Camundongos Endogâmicos C57BL/anatomia & histologia , Dente/anatomia & histologia , Análise de Componente Principal , Especificidade da Espécie , Masculino
7.
Folia Biol (Praha) ; 70(1): 45-52, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38830122

RESUMO

Effective treatment of patients with autism spectrum disorder (ASD) is still absent so far. Taurine exhibits therapeutic effects towards the autism-like behaviour in ASD model animals. Here, we determined the mechanism of taurine effect on hippocampal neurogenesis in genetically inbred BTBR T+ tf/J (BTBR) mice, a proposed model of ASD. In this ASD mouse model, we explored the effect of oral taurine supplementation on ASD-like behaviours in an open field test, elevated plus maze, marble burying test, self-grooming test, and three-chamber test. The mice were divided into four groups of normal controls (WT) and models (BTBR), who did or did not receive 6-week taurine supplementation in water (WT, WT+ Taurine, BTBR, and BTBR+Taurine). Neurogenesis-related effects were determined by Ki67 immunofluorescence staining. Western blot analysis was performed to detect the expression of phosphatase and tensin homologue deleted from chromosome 10 (PTEN)/mTOR/AKT pathway-associated proteins. Our results showed that taurine improved the autism-like behaviour, increased the proliferation of hippocampal cells, promoted PTEN expression, and reduced phosphorylation of mTOR and AKT in hippocampal tissue of the BTBR mice. In conclusion, taurine reduced the autism-like behaviour in partially inherited autism model mice, which may be associa-ted with improving the defective neural precursor cell proliferation and enhancing the PTEN-associated pathway in hippocampal tissue.


Assuntos
Transtorno Autístico , Hipocampo , Neurogênese , PTEN Fosfo-Hidrolase , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Serina-Treonina Quinases TOR , Taurina , Animais , Taurina/farmacologia , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Transtorno Autístico/metabolismo , Transtorno Autístico/tratamento farmacológico , Masculino , Comportamento Animal/efeitos dos fármacos , Camundongos , Modelos Animais de Doenças , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos
8.
Drug Res (Stuttg) ; 74(5): 241-249, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38830372

RESUMO

Pentoxifylline (PTX), a non-selective phosphodiesterase inhibitor, has demonstrated protective effects against lung injury in animal models. Given the significance of pulmonary toxicity resulting from paraquat (PQ) exposure, the present investigation was designed to explore the impact of PTX on PQ-induced pulmonary oxidative impairment in male mice.Following preliminary studies, thirty-six mice were divided into six groups. Group 1 received normal saline, group 2 received a single dose of PQ (20 mg/kg; i.p.), and group 3 received PTX (100 mg/kg/day; i.p.). Additionally, treatment groups 4-6 were received various doses of PTX (25, 50, and 100 mg/kg/day; respectively) one hour after a single dose of PQ. After 72 hours, the animals were sacrificed, and lung tissue was collected.PQ administration caused a significant decrease in hematocrit and an increase in blood potassium levels. Moreover, a notable increase was found in the lipid peroxidation (LPO), nitric oxide (NO), and myeloperoxidase (MPO) levels, along with a notable decrease in total thiol (TTM) and total antioxidant capacity (TAC) contents, catalase (CAT) and superoxide dismutase (SOD) enzymes activity in lung tissue. PTX demonstrated the ability to improve hematocrit levels; enhance SOD activity and TTM content; and decrease MPO activity, LPO and NO levels in PQ-induced pulmonary toxicity. Furthermore, these findings were well-correlated with the observed lung histopathological changes.In conclusion, our results suggest that the high dose of PTX may ameliorate lung injury by improving the oxidant/antioxidant balance in animals exposed to PQ.


Assuntos
Antioxidantes , Peroxidação de Lipídeos , Pulmão , Paraquat , Pentoxifilina , Superóxido Dismutase , Animais , Pentoxifilina/farmacologia , Pentoxifilina/uso terapêutico , Paraquat/toxicidade , Camundongos , Masculino , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Antioxidantes/farmacologia , Superóxido Dismutase/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Catalase/metabolismo , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/uso terapêutico , Óxido Nítrico/metabolismo , Peroxidase/metabolismo , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/tratamento farmacológico , Diester Fosfórico Hidrolases/metabolismo
9.
Med Oncol ; 41(7): 167, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38831079

RESUMO

Cancer stem cells (CSCs) are mainly responsible for tumorigenesis, chemoresistance, and cancer recurrence. CSCs growth and progression are regulated by multiple signaling cascades including Wnt/ß-catenin and Hh/GLI-1, which acts independently or via crosstalk. Targeting the crosstalk of signaling pathways would be an effective approach to control the CSC population. Both Wnt/ß-catenin and Hh/GLI-1 signaling cascades are known to be regulated by p53/p21-dependent mechanism. However, it is interesting to delineate whether p21 can induce apoptosis in a p53-independent manner. Therefore, utilizing various subtypes of oral CSCs (SCC9-PEMT p53+/+p21+/+, SCC9-PEMT p53-/-p21+/+, SCC9-PEMT p53+/+p21-/- and SCC9-PEMT p53-/-p21-/-), we have examined the distinct roles of p53 and p21 in Resveratrol nanoparticle (Res-Nano)-mediated apoptosis. It is interesting to see that, besides the p53/p21-mediated mechanism, Res-Nano exposure also significantly induced apoptosis in oral CSCs through a p53-independent activation of p21. Additionally, Res-Nano-induced p21-activation deregulated the ß-catenin-GLI-1 complex and consequently reduced the TCF/LEF and GLI-1 reporter activities. In agreement with in vitro data, similar experimental results were obtained in in vivo mice xenograft model.


Assuntos
Apoptose , Inibidor de Quinase Dependente de Ciclina p21 , Neoplasias Bucais , Nanopartículas , Células-Tronco Neoplásicas , Resveratrol , Proteína Supressora de Tumor p53 , Proteína GLI1 em Dedos de Zinco , beta Catenina , Apoptose/efeitos dos fármacos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Resveratrol/farmacologia , Proteína GLI1 em Dedos de Zinco/metabolismo , Proteína GLI1 em Dedos de Zinco/genética , beta Catenina/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Humanos , Neoplasias Bucais/patologia , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/metabolismo , Animais , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/genética , Camundongos , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Neuropathol Appl Neurobiol ; 50(3): e12992, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38831600

RESUMO

PURPOSE: Radiation-induced brain injury, one of the side effects of cranial radiotherapy in tumour patients, usually results in durable and serious cognitive disorders. Microglia are important innate immune-effector cells in the central nervous system. However, the interaction between microglia and neurons in radiation-induced brain injury remains uncharacterised. METHODS AND MATERIALS: We established a microglia-neuron indirect co-culture model to assess the interaction between them. Microglia exposed to radiation were examined for pyroptosis using lactate dehydrogenase (LDH) release, Annexin V/PI staining, SYTOX staining and western blot. The role of nucleotide-binding oligomerisation domain-like receptor family pyrin domain containing 3 (NLRP3) was investigated in microglia exposed to radiation and in mouse radiation brain injury model through siRNA or inhibitor. Mini-mental state examination and cytokines in blood were performed in 23 patients who had experienced cranial irradiation. RESULTS: Microglia exerted neurotoxic features after radiation in the co-culture model. NLRP3 was up-regulated in microglia exposed to radiation, and then caspase-1 was activated. Thus, the gasdermin D protein was cleaved, and it triggered pyroptosis in microglia, which released inflammatory cytokines. Meanwhile, treatment with siRNA NLRP3 in vitro and NLRP3 inhibitor in vivo attenuated the damaged neuron cell and cognitive impairment, respectively. What is more, we found that the patients after radiation with higher IL-6 were observed to have a decreased MMSE score. CONCLUSIONS: These findings indicate that radiation-induced pyroptosis in microglia may promote radiation-induced brain injury via the secretion of neurotoxic cytokines. NLRP3 was evaluated as an important mediator in radiation-induced pyroptosis and a promising therapeutic target for radiation-induced brain injury.


Assuntos
Lesões Encefálicas , Microglia , Proteína 3 que Contém Domínio de Pirina da Família NLR , Piroptose , Piroptose/efeitos da radiação , Piroptose/fisiologia , Microglia/metabolismo , Microglia/efeitos da radiação , Microglia/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Camundongos , Humanos , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Lesões Encefálicas/etiologia , Masculino , Neurônios/metabolismo , Neurônios/patologia , Neurônios/efeitos da radiação , Técnicas de Cocultura , Lesões por Radiação/patologia , Lesões por Radiação/metabolismo , Feminino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade
11.
J Comp Neurol ; 532(6): e25619, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38831653

RESUMO

Zebrafish is a useful model organism in neuroscience; however, its gene expression atlas in the adult brain is not well developed. In the present study, we examined the expression of 38 neuropeptides, comparing with GABAergic and glutamatergic neuron marker genes in the adult zebrafish brain by comprehensive in situ hybridization. The results are summarized as an expression atlas in 19 coronal planes of the forebrain. Furthermore, the scanned data of all brain sections were made publicly available in the Adult Zebrafish Brain Gene Expression Database (https://ssbd.riken.jp/azebex/). Based on these data, we performed detailed comparative neuroanatomical analyses of the hypothalamus and found that several regions previously described as one nucleus in the reference zebrafish brain atlas contain two or more subregions with significantly different neuropeptide/neurotransmitter expression profiles. Subsequently, we compared the expression data in zebrafish telencephalon and hypothalamus obtained in this study with those in mice, by performing a cluster analysis. As a result, several nuclei in zebrafish and mice were clustered in close vicinity. The present expression atlas, database, and anatomical findings will contribute to future neuroscience research using zebrafish.


Assuntos
Neuropeptídeos , Prosencéfalo , Peixe-Zebra , Animais , Peixe-Zebra/anatomia & histologia , Prosencéfalo/metabolismo , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Atlas como Assunto , Expressão Gênica , Bases de Dados Genéticas , Camundongos
12.
Cancer Res ; 84(11): 1742-1744, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38831750

RESUMO

Obesity has been linked to prostate cancer in a stage-dependent manner, having no association with cancer initiation but correlating with disease progression in men with prostate cancer. Given the rising obesity rate and its association to aggressive prostate cancer, there is a growing need to understand the mechanisms underlying this relationship to identify patients at increased risk of lethal disease and inform therapeutic approaches. In this issue of Cancer Research, Boufaied and colleagues describe how diets high in saturated fatty acids promote MYC-driven prostate cancer. Leveraging MYC-expressing genetically engineered and allograft mouse models fed either a control low-fat or high-fat diet (HFD) enriched in saturated fatty acids, the authors found using digital pathology that HFD-fed mice exhibited increased tumor invasion. Metabolomics, transcriptomics, immunoblotting, and positron emission tomography of tumors from these mice demonstrated that a HFD promoted a metabolic shift in the tumors towards glycolysis. These preclinical data were supported by findings from two large clinical cohorts revealing that men diagnosed with prostate cancer and who consumed high levels of saturated fatty acids possessed tumors bearing glycolytic signatures. Deconvolution analyses and immunohistochemistry validation showed that these tumors also displayed increased angiogenesis and infiltration of immunosuppressive macrophages and regulatory T cells, the latter of which was also correlated with high saturated fat intake-associated glycolytic signatures in patient tumors. Together, these findings suggest that diets rich in saturated fatty acids, rather than obesity alone, accelerate MYC-driven prostate cancers through shifting tumor metabolism and shaping the tumor microenvironment. See related article by Boufaied et al., p. 1834.


Assuntos
Dieta Hiperlipídica , Neoplasias da Próstata , Microambiente Tumoral , Masculino , Neoplasias da Próstata/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Animais , Humanos , Camundongos , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos/metabolismo , Obesidade/metabolismo , Obesidade/genética , Glicólise
13.
Cell Mol Life Sci ; 81(1): 248, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38832964

RESUMO

Contractile actomyosin bundles play crucial roles in various physiological processes, including cell migration, morphogenesis, and muscle contraction. The intricate assembly of actomyosin bundles involves the precise alignment and fusion of myosin II filaments, yet the underlying mechanisms and factors involved in these processes remain elusive. Our study reveals that LUZP1 plays a central role in orchestrating the maturation of thick actomyosin bundles. Loss of LUZP1 caused abnormal cell morphogenesis, migration, and the ability to exert forces on the environment. Importantly, knockout of LUZP1 results in significant defects in the concatenation and persistent association of myosin II filaments, severely impairing the assembly of myosin II stacks. The disruption of these processes in LUZP1 knockout cells provides mechanistic insights into the defective assembly of thick ventral stress fibers and the associated cellular contractility abnormalities. Overall, these results significantly contribute to our understanding of the molecular mechanism involved in actomyosin bundle formation and highlight the essential role of LUZP1 in this process.


Assuntos
Actomiosina , Movimento Celular , Contração Muscular , Miosina Tipo II , Actomiosina/metabolismo , Humanos , Contração Muscular/fisiologia , Miosina Tipo II/metabolismo , Miosina Tipo II/genética , Animais , Citoesqueleto de Actina/metabolismo , Camundongos
14.
J Nanobiotechnology ; 22(1): 303, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38822376

RESUMO

Radiation-induced intestinal injury is the most common side effect during radiotherapy of abdominal or pelvic solid tumors, significantly impacting patients' quality of life and even resulting in poor prognosis. Until now, oral application of conventional formulations for intestinal radioprotection remains challenging with no preferred method available to mitigate radiation toxicity in small intestine. Our previous study revealed that nanomaterials derived from spore coat of probiotics exhibit superior anti-inflammatory effect and even prevent the progression of cancer. The aim of this work is to determine the radioprotective effect of spore coat (denoted as spore ghosts, SGs) from three clinically approved probiotics (B.coagulans, B.subtilis and B.licheniformis). All the three SGs exhibit outstanding reactive oxygen species (ROS) scavenging ability and excellent anti-inflammatory effect. Moreover, these SGs can reverse the balance of intestinal flora by inhibiting harmful bacteria and increasing the abundance of Lactobacillus. Consequently, administration of SGs significantly reduce radiation-induced intestinal injury by alleviating diarrhea, preventing X-ray induced apoptosis of small intestinal epithelial cells and promoting restoration of barrier integrity in a prophylactic study. Notably, SGs markedly improve weight gain and survival of mice received total abdominal X-ray radiation. This work may provide promising radioprotectants for efficiently attenuating radiation-induced gastrointestinal syndrome and promote the development of new intestinal predilection.


Assuntos
Probióticos , Protetores contra Radiação , Esporos Bacterianos , Animais , Probióticos/farmacologia , Camundongos , Administração Oral , Protetores contra Radiação/farmacologia , Protetores contra Radiação/uso terapêutico , Protetores contra Radiação/química , Esporos Bacterianos/efeitos da radiação , Lesões por Radiação/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Intestino Delgado/microbiologia , Intestino Delgado/efeitos da radiação , Intestino Delgado/patologia , Humanos , Apoptose/efeitos dos fármacos , Masculino , Microbioma Gastrointestinal/efeitos dos fármacos , Intestinos/efeitos da radiação , Intestinos/microbiologia , Intestinos/patologia , Lesões Experimentais por Radiação/patologia
15.
Commun Biol ; 7(1): 674, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38824207

RESUMO

Studying cellular mechanoresponses during cancer metastasis is limited by sample variation or complex protocols that current techniques require. Metastasis is governed by mechanotransduction, whereby cells translate external stimuli, such as circulatory fluid shear stress (FSS), into biochemical cues. We present high-throughput, semi-automated methods to expose cells to FSS using the VIAFLO96 multichannel pipetting device custom-fitted with 22 G needles, increasing the maximum FSS 94-fold from the unmodified tips. Specifically, we develop protocols to semi-automatically stain live samples and to fix, permeabilize, and intracellularly process cells for flow cytometry analysis. Our first model system confirmed that the pro-apoptotic effects of TRAIL therapeutics in prostate cancer cells can be enhanced via FSS-induced Piezo1 activation. Our second system implements this multiplex methodology to show that FSS exposure (290 dyn cm-2) increases activation of murine bone marrow-derived dendritic cells. These methodologies greatly improve the mechanobiology workflow, offering a high-throughput, multiplex approach.


Assuntos
Mecanotransdução Celular , Neoplasias da Próstata , Animais , Humanos , Camundongos , Neoplasias da Próstata/patologia , Neoplasias da Próstata/imunologia , Masculino , Células Dendríticas/imunologia , Linhagem Celular Tumoral , Ensaios de Triagem em Larga Escala/métodos , Estresse Mecânico , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Citometria de Fluxo/métodos , Canais Iônicos
16.
J Neuroinflammation ; 21(1): 146, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38824594

RESUMO

T cells play an important role in the acquired immune response, with regulatory T cells (Tregs) serving as key players in immune tolerance. Tregs are found in nonlymphoid and damaged tissues and are referred to as "tissue Tregs". They have tissue-specific characteristics and contribute to immunomodulation, homeostasis, and tissue repair through interactions with tissue cells. However, important determinants of Treg tissue specificity, such as antigen specificity, tissue environment, and pathology, remain unclear. In this study, we analyzed Tregs in the central nervous system of mice with ischemic stroke and experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. The gene expression pattern of brain Tregs in the EAE model was more similar to that of ischemic stroke Tregs in the brain than to that of spinal cord Tregs. In addition, most T-cell receptors (TCRs) with high clonality were present in both the brain and spinal cord. Furthermore, Gata3+ and Rorc+ Tregs expressed TCRs recognizing MOG in the spinal cord, suggesting a tissue environment conducive to Rorc expression. Tissue-specific chemokine/chemokine receptor interactions in the spinal cord and brain influenced Treg localization. Finally, spinal cord- or brain-derived Tregs had greater anti-inflammatory capacities in EAE mice, respectively. Taken together, these findings suggest that the tissue environment, rather than pathogenesis or antigen specificity, is the primary determinant of the tissue-specific properties of Tregs. These findings may contribute to the development of novel therapies to suppress inflammation through tissue-specific Treg regulation.


Assuntos
Encéfalo , Encefalomielite Autoimune Experimental , Camundongos Endogâmicos C57BL , Medula Espinal , Linfócitos T Reguladores , Animais , Linfócitos T Reguladores/imunologia , Camundongos , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Medula Espinal/imunologia , Medula Espinal/patologia , Medula Espinal/metabolismo , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/patologia , Feminino , Modelos Animais de Doenças
17.
PeerJ ; 12: e17427, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38827289

RESUMO

Background: Survivors of sepsis may encounter cognitive impairment following their recovery from critical condition. At present, there is no standardized treatment for addressing sepsis-associated encephalopathy. Lactobacillus rhamnosus GG (LGG) is a prevalent bacterium found in the gut microbiota and is an active component of probiotic supplements. LGG has demonstrated to be associated with cognitive improvement. This study explored whether LGG administration prior to and following induced sepsis could ameliorate cognitive deficits, and explored potential mechanisms. Methods: Female C57BL/6 mice were randomly divided into three groups: sham surgery, cecal ligation and puncture (CLP), and CLP+LGG. Cognitive behavior was assessed longitudinally at 7-9d, 14-16d, and 21-23d after surgery using an open field test and novel object recognition test. The impact of LGG treatment on pathological changes, the expression level of brain-derived neurotrophic factor (BDNF), and the phosphorylation level of the TrkB receptor (p-TrkB) in the hippocampus of mice at two weeks post-CLP (16d) were evaluated using histological, immunofluorescence, immunohistochemistry, and western blot analyses. Results: The CLP surgery induced and sustained cognitive impairment in mice with sepsis for a minimum of three weeks following the surgery. Compared to mice subjected to CLP alone, the administration of LGG improved the survival of mice with sepsis and notably enhanced their cognitive functioning. Moreover, LGG supplementation significantly alleviated the decrease in hippocampal BDNF expression and p-TrkB phosphorylation levels caused by sepsis, preserving neuronal survival and mitigating the pathological changes within the hippocampus of mice with sepsis. LGG supplementation mitigates sepsis-related cognitive impairment in mice and preserves BDNF expression and p-TrkB levels in the hippocampus.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Disfunção Cognitiva , Hipocampo , Lacticaseibacillus rhamnosus , Camundongos Endogâmicos C57BL , Probióticos , Sepse , Animais , Sepse/complicações , Sepse/terapia , Sepse/microbiologia , Sepse/metabolismo , Disfunção Cognitiva/terapia , Disfunção Cognitiva/etiologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Feminino , Camundongos , Hipocampo/metabolismo , Probióticos/farmacologia , Probióticos/administração & dosagem , Probióticos/uso terapêutico , Modelos Animais de Doenças , Receptor trkB/metabolismo , Encefalopatia Associada a Sepse/metabolismo , Encefalopatia Associada a Sepse/patologia , Encefalopatia Associada a Sepse/dietoterapia , Fosforilação
18.
PeerJ ; 12: e17280, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38827298

RESUMO

Cuproptosis-related key genes play a significant role in the pathological processes of acute myocardial infarction (AMI). However, a complete understanding of the molecular mechanisms behind this participation remains elusive. This study was designed to identify genes and immune cells critical to AMI pathogenesis. Based on the GSE48060 dataset (31 AMI patients and 21 healthy persons, GPL570-55999), we identified genes associated with dysregulated cuproptosis and the activation of immune responses between normal subjects and patients with a first myocardial attack. Two molecular clusters associated with cuproptosis were defined in patients with AMI. Immune infiltration analysis showed that there was significant immunity heterogeneity among different clusters. Multiple immune responses were closely associated with Cluster2-specific differentially expressed genes (DEGs). The generalized linear model machine model presented the best discriminative performance with relatively lower residual and root mean square error, and a higher area under the curve (AUC = 0.870). A final two-gene-based generalized linear model was constructed, exhibiting satisfactory performance in two external validation datasets (AUC = 0.719, GSE66360 and AUC = 0.856, GSE123342). Column graph, calibration curve, and decision curve analyses also proved the accuracy of AMI prediction. We also constructed a mouse C57BL/6 model of AMI (3 h, 48 h, and 1 week) and used qRT-PCR and immunofluorescence to detect the expression changes of CBLB and ZNF302. In this study, we present a systematic analysis of the complex relationship between cuproptosis and a first AMI attack, and provide new insights into the diagnosis and treatment of AMI.


Assuntos
Biologia Computacional , Modelos Animais de Doenças , Infarto do Miocárdio , Infarto do Miocárdio/genética , Animais , Camundongos , Biologia Computacional/métodos , Biomarcadores/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Perfilação da Expressão Gênica/métodos , Masculino
19.
PeerJ ; 12: e17488, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38827303

RESUMO

Epigallocatechin gallate (EGCG), an active constituent of tea, is recognized for its anticancer and anti-inflammatory properties. However, the specific mechanism by which EGCG protects osteoblasts from cadmium-induced damage remains incompletely understood. Here, the action of EGCG was investigated by exposing MC3T3-E1 osteoblasts to EGCG and CdCl2 and examining their growth, apoptosis, and differentiation. It was found that EGCG promoted the viability of cadmium-exposed MC3T3-E1 cells, mitigated apoptosis, and promoted both maturation and mineralization. Additionally, CdCl2 has been reported to inhibit both the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) and nuclear factor erythroid 2-related factor 2/heme oxygenase-1(Nrf2/HO-1) signaling pathways. EGCG treatment attenuated cadmium-induced apoptosis in osteoblasts and restored their function by upregulating both signaling pathways. The findings provide compelling evidence for EGCG's role in attenuating cadmium-induced osteoblast apoptosis and dysfunction through activating the PI3K/AKT/mTOR and Nrf2/HO-1 pathways. This suggests the potential of using EGCG for treating cadmium-induced osteoblast dysfunction.


Assuntos
Apoptose , Catequina , Heme Oxigenase-1 , Fator 2 Relacionado a NF-E2 , Osteoblastos , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Serina-Treonina Quinases TOR , Catequina/análogos & derivados , Catequina/farmacologia , Apoptose/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Camundongos , Serina-Treonina Quinases TOR/metabolismo , Transdução de Sinais/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Cádmio/toxicidade , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Proteínas de Membrana
20.
Oncol Res ; 32(6): 1079-1091, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38827318

RESUMO

Approximately 30%-40% of growth hormone-secreting pituitary adenomas (GHPAs) harbor somatic activating mutations in GNAS (α subunit of stimulatory G protein). Mutations in GNAS are associated with clinical features of smaller and less invasive tumors. However, the role of GNAS mutations in the invasiveness of GHPAs is unclear. GNAS mutations were detected in GHPAs using a standard polymerase chain reaction (PCR) sequencing procedure. The expression of mutation-associated maternally expressed gene 3 (MEG3) was evaluated with RT-qPCR. MEG3 was manipulated in GH3 cells using a lentiviral expression system. Cell invasion ability was measured using a Transwell assay, and epithelial-mesenchymal transition (EMT)-associated proteins were quantified by immunofluorescence and western blotting. Finally, a tumor cell xenograft mouse model was used to verify the effect of MEG3 on tumor growth and invasiveness. The invasiveness of GHPAs was significantly decreased in mice with mutated GNAS compared with that in mice with wild-type GNAS. Consistently, the invasiveness of mutant GNAS-expressing GH3 cells decreased. MEG3 is uniquely expressed at high levels in GHPAs harboring mutated GNAS. Accordingly, MEG3 upregulation inhibited tumor cell invasion, and conversely, MEG3 downregulation increased tumor cell invasion. Mechanistically, GNAS mutations inhibit EMT in GHPAs. MEG3 in mutated GNAS cells prevented cell invasion through the inactivation of the Wnt/ß-catenin signaling pathway, which was further validated in vivo. Our data suggest that GNAS mutations may suppress cell invasion in GHPAs by regulating EMT through the activation of the MEG3/Wnt/ß-catenin signaling pathway.


Assuntos
Cromograninas , Transição Epitelial-Mesenquimal , Subunidades alfa Gs de Proteínas de Ligação ao GTP , Adenoma Hipofisário Secretor de Hormônio do Crescimento , Mutação , Invasividade Neoplásica , RNA Longo não Codificante , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Animais , Humanos , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Camundongos , Cromograninas/genética , Cromograninas/metabolismo , Transição Epitelial-Mesenquimal/genética , RNA Longo não Codificante/genética , Feminino , Masculino , Linhagem Celular Tumoral , Adenoma/genética , Adenoma/patologia , Adenoma/metabolismo , Pessoa de Meia-Idade , Adulto , Proliferação de Células/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Via de Sinalização Wnt/genética , Regulação Neoplásica da Expressão Gênica
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...